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Revision as of 09:17, 25 October 2011 editBeetstra (talk | contribs)Edit filter managers, Administrators172,031 edits Script assisted update of identifiers for the Chem/Drugbox validation project (updated: 'CAS_number').← Previous edit		Latest revision as of 13:05, 15 December 2024 edit undoBoghog (talk | contribs)Autopatrolled, Extended confirmed users, IP block exemptions, New page reviewers, Pending changes reviewers, Rollbackers, Template editors137,800 edits consistent citation formatting
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			{{Short description|Chemical compound}}
	{{Drugbox
			{{cs1 config|name-list-style=vanc|display-authors=6}}
			{{Infobox drug
	| Verifiedfields = changed		| Verifiedfields = changed
	| verifiedrevid = 407820545		| verifiedrevid = 457288866
	| IUPAC_name = 4,5,6,7-tetrahydroisoxazolopyridin-3(2''H'')-one		| IUPAC_name = 4,5,6,7-tetrahydroisoxazolopyridin-3(2''H'')-one
	| image = Gaboxadol.svg		| image = Gaboxadol.svg
			| width =
	<!--Clinical data-->		<!--Clinical data-->
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	| legal_US = <!-- OTC / Rx-only / Schedule I, II, III, IV, V -->		| legal_US = <!-- OTC / Rx-only / Schedule I, II, III, IV, V -->
	| legal_status =		| legal_status =
	| routes_of_administration =		| routes_of_administration =
	<!--Pharmacokinetic data-->		<!--Pharmacokinetic data-->
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	| metabolism =		| metabolism =
	| elimination_half-life =		| elimination_half-life =
	| excretion =		| excretion =
	<!--Identifiers-->		<!--Identifiers-->
	| CAS_number_Ref = {{cascite|correct|??}}		| IUPHAR_ligand = 4322
			| CAS_number_Ref = {{cascite|correct|CAS}}
	| CAS_number = <!-- blanked - oldvalue: 64603-91-4 -->		| CAS_number = 64603-91-4
	| ATC_prefix = none		| ATC_prefix = none
	| ATC_suffix =		| ATC_suffix =
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	| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}		| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
	| ChemSpiderID = 3330		| ChemSpiderID = 3330
	| UNII_Ref = {{fdacite|changed|FDA}}		| UNII_Ref = {{fdacite|correct|FDA}}
	| UNII = K1M5RVL18S		| UNII = K1M5RVL18S
	| KEGG_Ref = {{keggcite|correct|kegg}}		| KEGG_Ref = {{keggcite|correct|kegg}}
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	| ChEMBL_Ref = {{ebicite|correct|EBI}}		| ChEMBL_Ref = {{ebicite|correct|EBI}}
	| ChEMBL = 312443		| ChEMBL = 312443
			| synonyms = THIP; OV101; OV-101
	<!--Chemical data-->		<!--Chemical data-->
	| C=6 | H=8 | N=2 | O=2		| C=6 | H=8 | N=2 | O=2
		⚫	| SMILES = O=C1/C2=C(\ON1)CNCC2
	| molecular_weight = 140.14 g/mol
⚫	| smiles = O=C1/C2=C(\ON1)CNCC2
	| InChI = 1/C6H8N2O2/c9-6-4-1-2-7-3-5(4)10-8-6/h7H,1-3H2,(H,8,9)
	| InChIKey = ZXRVKCBLGJOCEE-UHFFFAOYAU
	| StdInChI_Ref = {{stdinchicite|correct|chemspider}}		| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
	| StdInChI = 1S/C6H8N2O2/c9-6-4-1-2-7-3-5(4)10-8-6/h7H,1-3H2,(H,8,9)		| StdInChI = 1S/C6H8N2O2/c9-6-4-1-2-7-3-5(4)10-8-6/h7H,1-3H2,(H,8,9)
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	}}		}}
	'''Gaboxadol''' also known as 4,5,6,7-'''t'''etra'''h'''ydro'''i'''soxazolo(5,4-c)'''p'''yridin-3-ol ('''THIP''') is an experimental sleep aid drug developed by ] and ]<ref>US Patent 4278676 - Heterocyclic compounds</ref>. In March, 2007, Merck and H. Lundbeck cancelled work on the drug, citing safety concerns and the failure of an efficacy trial. It acts on the ] system, but in a very different way from ]s and ]s (], ], etc).{{Citation needed|date=October 2010}} Lundbeck states that gaboxadol also increases ] (stage 4).		'''Gaboxadol''', also known as 4,5,6,7-<u>t</u>etra<u>h</u>ydro<u>i</u>soxazolo(5,4-c)<u>p</u>yridin-3-ol ('''THIP'''), is a conformationally constrained derivative of the ] ] that was first synthesized in 1977 by the Danish ] Poul Krogsgaard-Larsen.<ref name=Hamilton>{{cite magazine|url=http://harpers.org/archive/2013/08/gaboxadol/ |title=Gaboxadol | vauthors = Morris H |magazine=Harper's Magazine |date=August 2013 |access-date=2014-11-20}}</ref> In the early 1980s gaboxadol was the subject of a series of ] that tested its efficacy as an analgesic and anxiolytic, as well as a treatment for ], ], ], and ].<ref name="Hamilton"/> It was not until 1996 that researchers attempted to harness gaboxadol's frequently reported sedative "]" for the treatment of insomnia, resulting in a series of clinical trials sponsored by ] and ].<ref name="Hamilton"/><ref>{{cite patent | country = US | number = 4278676 | title = Heterocyclic compounds | assign = H Lundbeck AS | inventor = Krogsgaard-Larsen P | gdate = 14 July 1981 }}</ref> In March, 2007, Merck and Lundbeck cancelled work on the drug, citing safety concerns and the failure of an efficacy trial. It acts on the ] system, but in a different way from ]s, ], and ]s. Lundbeck states that gaboxadol also increases ] (stage 4). Unlike ], gaboxadol does not demonstrate ] in mice or baboons despite activation of ] in the ].<ref>{{cite journal | vauthors = Vashchinkina E, Panhelainen A, Vekovischeva OY, Aitta-aho T, Ebert B, Ator NA, Korpi ER | title = GABA site agonist gaboxadol induces addiction-predicting persistent changes in ventral tegmental area dopamine neurons but is not rewarding in mice or baboons | journal = The Journal of Neuroscience | volume = 32 | issue = 15 | pages = 5310–20 | date = April 2012 | pmid = 22496576 | doi = 10.1523/JNEUROSCI.4697-11.2012 | pmc = 6622081 | doi-access = free }}</ref>
			In 2015, Lundbeck sold its rights to the molecule to Ovid Therapeutics, whose plan is to develop it for ] and ].<ref name=CNBC>{{cite web|url=https://www.cnbc.com/2015/04/16/former-teva-ceos-new-gig-at-ovid-therapeutics.html |title=Former Teva CEO's new gig at Ovid Therapeutics | vauthors = Tirrell M |publisher=CNBC |date=16 April 2015 |access-date=2015-05-06}}</ref> It is known internally in Ovid as '''OV101'''.
			== Pharmacology ==
			Gaboxadol is a supra-maximal agonist at ], low-potency agonist at α<sub>1</sub>β<sub>3</sub>γ<sub>2</sub>, partial agonist at α<sub>4</sub>β<sub>3</sub>γ, and antagonist at ] ] receptors.<ref>{{cite journal | vauthors = Brown N, Kerby J, Bonnert TP, Whiting PJ, Wafford KA | title = Pharmacological characterization of a novel cell line expressing human alpha(4)beta(3)delta GABA(A) receptors | journal = British Journal of Pharmacology | volume = 136 | issue = 7 | pages = 965–974 | date = August 2002 | pmid = 12145096 | pmc = 1573424 | doi = 10.1038/sj.bjp.0704795 }}</ref><ref>{{Cite journal | vauthors = Orser BA |date=2006-04-15 |title=Extrasynaptic GABAA Receptors Are Critical Targets for Sedative-Hypnotic Drugs |journal=Journal of Clinical Sleep Medicine |language=en |volume=02 |issue=2 |doi=10.5664/jcsm.26526 |issn=1550-9389|doi-access=free }}</ref><ref name=":0">{{cite journal | vauthors = Johnston GA | title = Muscimol as an ionotropic GABA receptor agonist | journal = Neurochemical Research | volume = 39 | issue = 10 | pages = 1942–1947 | date = October 2014 | pmid = 24473816 | doi = 10.1007/s11064-014-1245-y }}</ref> Its affinity for extrasynaptic ] receptors is 10-fold greater than other subtypes.<ref>{{cite journal | vauthors = Rudolph U, Knoflach F | title = Beyond classical benzodiazepines: novel therapeutic potential of GABAA receptor subtypes | journal = Nature Reviews. Drug Discovery | volume = 10 | issue = 9 | pages = 685–697 | date = July 2011 | pmid = 21799515 | pmc = 3375401 | doi = 10.1038/nrd3502 }}</ref> Gaboxadol has a unique affinity for extrasynaptic α<sub>4</sub>β<sub>3</sub>δ GABA<sub>A</sub> receptors, which mediate tonic inhibition and are typically activated by ambient, low levels of GABA in the extrasynaptic space.<ref>{{cite journal | vauthors = Mortensen M, Ebert B, Wafford K, Smart TG | title = Distinct activities of GABA agonists at synaptic- and extrasynaptic-type GABAA receptors | journal = The Journal of Physiology | volume = 588 | issue = Pt 8 | pages = 1251–1268 | date = April 2010 | pmid = 20176630 | pmc = 2872731 | doi = 10.1113/jphysiol.2009.182444 }}</ref>
			Compared to muscimol, gaboxadol binds less potently to α<sub>4</sub>β<sub>3</sub>δ GABA<sub>A</sub> receptors (EC<sub>50</sub> .2μM vs 13μM), but is capable of evoking a greater maximum response (] 120% vs 224%).<ref name=":0" /> The supra-maximial efficacy of gabaxadol at α<sub>4</sub>β<sub>3</sub>δ GABA<sub>A</sub> receptors has been attributed to an increase in the duration and frequency of channel openings relative to the endogenous agonist GABA.<ref name=":0" />
			== Clinical studies ==
			Gaboxadol produced effects in ] including ], ], and ] or ] changes.<ref name="Krogsgaard-LarsenFrølundLiljefors2006">{{cite journal | vauthors = Krogsgaard-Larsen P, Frølund B, Liljefors T | title = GABA(A) agonists and partial agonists: THIP (Gaboxadol) as a non-opioid analgesic and a novel type of hypnotic | journal = Adv Pharmacol | volume = 54 | issue = | pages = 53–71 | date = 2006 | pmid = 17175810 | doi = 10.1016/s1054-3589(06)54003-7 | url = | quote = In cancer patients and also in patients with chronic anxiety (Hoehn‐Saric, 1983) the desired effects of Gaboxadol were accompanied by side effects, notably sedation, nausea, and in a few cases euphoria. The side effects of Gaboxadol have, however, been described as mild and similar in quality to those of other GABA‐mimetics (Hoehn‐Saric, 1983). This combination of analgesic and anxiolytic effects of THIP obviously has therapeutic prospects.}}</ref><ref name="SchoedelRosenAlexander2009">{{cite journal | vauthors = Schoedel KA, Rosen LB, Alexander R, Wang J, Snavely D, Murphy MG, Chodakewitz J, Mengel H, Romach MK, Sellers EM | title=Poster Session I (PI 1-89): PI-44: A single-dose randomized, double-blind, crossover abuse liability study to evaluate the subjective and objective effects of gaboxadol and zolpidem in recreational drug users | journal=Clinical Pharmacology & Therapeutics | volume=85 | issue=S1 | date=16 January 2009 | issn=0009-9236 | doi=10.1038/sj.clpt.2008.283 | pages=S9–S36 (S22–S22) | url = }}</ref> It showed less euphoria and ], more negative and dissociative effects, and fewer sedative effects than ] at the assessed doses.<ref name="SchoedelRosenAlexander2009" />
	== See also ==		== See also ==
	* ]		* ]
			* '']''
			* ]
			* ]
			* ]
	== References ==		== References ==
	{{Reflist|2}}		{{Reflist}}
	== External links ==		== External links ==
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	*		*
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	* .		* .
			*
	{{Depressants}}
	{{Hypnotics and sedatives}}		{{Hypnotics and sedatives}}
	{{GABAergics}}		{{GABAergics}}
			{{Glycinergics}}
			]
			]
			]
	]		]
	]		]
			]
			]
	{{sedative-stub}}
	]